Renal Manifestations of IgG4-Related Disease: A Concise Review

IgG4-related disease (IgG4-RD) is an immune-mediated disorder marked by fibro-inflammatory masses that can infiltrate multiple organ systems. Due to its relatively recent discovery and limited understanding of its pathophysiology, IgG4-related disease may be difficult to recognize and is consequently potentially underdiagnosed. Renal involvement is becoming regarded as one of the key features of this disease. To date, the most well-recognized renal complication of IgG4-related disease is tubulointerstitial nephritis, but membranous glomerulonephritis, renal masses, and retroperitoneal fibrosis have also been reported. This concise review has two objectives. First, it will briefly encapsulate the history, epidemiology, and presentation of IgG4-related disease. Second, it will examine the reported renal manifestations of IgG4-related disease, exploring the relevant histology, imaging, clinical features, and treatment considerations. This synthesis will be highly relevant for nephrologists, rheumatologists, general internists, and renal pathologists to raise awareness and help improve early recognition of IgG4-related kidney disease (IgG4-RKD).

Renal involvement is now regarded as one of the key features of this disease.In 2004, the frst reports of an association between Type 1 autoimmune pancreatitis and renal dysfunction were identifed [30,31].Since that time, renal dysfunction has also been associated with Mikulicz's syndrome [32], IgG4-related hepatic involvement [33], and other extra-renal IgG4-RD syndromes [34,35].In these initial reports, renal involvement is manifested as tubulointerstitial nephritis, which to date is still the most wellrecognized renal manifestation of IgG4-RD [34,36].However, glomerular involvement has also been described-membranous glomerulonephritis is the primary glomerular injury pattern noted in the literature [37,38].Additional described manifestations include renal masses [39,40] and retroperitoneal fbrosis that can secondarily afect the renal system [41,42].Te diversity of potential manifestations in the kidney has led to more encompassing terminology entitled IgG4-related kidney disease (IgG4-RKD) [43].Te frst set of IgG4-RKD diagnostic criteria was proposed in 2011 by Kawano and colleagues [43].An updated version by Saeki and colleagues was proposed in 2020 and is enclosed in Table 1 [44].In practice, tissue examination by means of renal biopsy in combination with clinical, laboratory, and imaging features is used to confrm the diagnosis of IgG4-RKD.Storiform fbrosis under the microscope is depicted in Figures 1 and 2.

Presentation
IgG4-RD is an uncommon disorder.Tere are few objective data available regarding international prevalence and incidence.IgG4-RD is most extensively studied in Japan, where national estimates of prevalence and incidence range between 8,000 and 10,000 afected persons and 0.28-1.08/100,000 population, respectively [45,46].However, IgG4-RD has been reported across racial and ethnic groups, and it is likely underrecognized in other parts of the world [47].Te peak age of afected individuals is between 50 and 70 years old with a male predominance [45,47].Among patients with IgG4-RKD, it appears that renal involvement is typically accompanied by involvement at other extra-renal sites [34,43,48].
Comprehensive diagnostic criteria for IgG4-RD incorporating histology with clinical, serologic, and imaging features are now available.Te frst set of criteria came from content experts in Japan in 2011 [55] and was recently revised in 2020 [56].Teir approach uses the presence or absence of key disease features to assign the diagnosis as defnite, probable, or possible.Te second set of criteria comes from the American College of Rheumatology/European League Against Rheumatism in 2019 as the IgG4-RD Classifcation Criteria [57].Tis latter approach is constructed in a stepwise fashion.Entry criteria and exclusion criteria must be reviewed before inclusion criteria are scored using a points-based system.Total inclusion points >20 are considered to meet the classifcation criteria for IgG4-RD.Both criteria are discussed in greater detail in these respective articles [55][56][57].
In the kidney, IgG4-RD frequently presents a diagnostic challenge.Tubulointerstitial, glomerular, and perirenal involvements may all be noted and may mimic other autoimmune and neoplastic diseases.It is, therefore, imperative for the clinician and the pathologist to maintain appropriate clinical suspicion of IgG4-RD and its renal manifestations.Serologically, elevated serum IgG4 and IgE levels with hypocomplementemia are consistent with IgG4-RKD [43,44].Radiologically, one of the most reliable fndings is the presence of multiple low-attenuation renal lesions on contrast-enhanced CT, as depicted in Figure 3.Additional fndings may include difuse kidney enlargement and solitary renal masses mimicking neoplasms, among others [43,58].Clinically, the onset and course of renal involvement can be acute but are generally slowly progressive [1,[59][60][61].Key renal manifestations are individually reviewed in subsequent paragraphs.

Tubulointerstitial Involvement
To date, the most well-recognized renal manifestation of IgG4-RD is tubulointerstitial nephritis (IgG4-TIN) [34,36,48,63].Two key biopsy series provided initial insights into this entity.In 2010, Saeki and colleagues demonstrated in a Japanese cohort that IgG4-TIN was male predominant with a mean age of 65 and that 95% of patients had associated extra-renal IgG4-RD manifestations [34].In 2011, Raissian and colleagues corroborated this in an American cohort [48].Teir fndings demonstrated that IgG4-TIN was male predominant with a mean age of 65 and that 83% of patients had associated extra-renal IgG4-RD manifestations.Hence, it appears that the demographics of IgG4-TIN mimic those of IgG4-RD as a whole.It also appears that IgG4-TIN is rarely present in isolation without other organ manifestations.Te subsequent literature has further supported these fndings [64][65][66].
Interestingly, IgG4-TIN difers from other forms of TIN in several distinct ways.First, unlike drug-induced TIN, IgG4-TIN does not appear to be associated with urinary excretion of white blood cell casts [64].Second, serum Creactive protein tends to be normal [34], which is hypothesized to result from relatively indolent and low-grade autoimmune activity.Tird, an elevated serum IgG4 concentration >135 mg/dL is observed in more than half of cases [43,48].Fourth, low-density renal lesions may be seen on enhanced CT [43,48].Fifth, and most importantly, International Journal of Nephrology histologic examination reveals unique tubulointerstitial features.Tese include storiform fbrosis plus prominent interstitial lymphoplasmacytic infltrates with increased numbers of IgG4 + plasma cells, typically >10/HPF and/or an IgG4 + /IgG ratio >40% [43].Te composition of cellular infltrates may change as the disease progresses, with a mixture of lymphocytes and plasma cells in the early stages and attenuation of infammatory cells with advanced fbrosis in the late stages [66].Additional suggestive histologic features include the following: well-demarcated borders, Table 1: Diagnostic criteria for IgG4-related kidney disease (IgG4-RKD) 2020 [44].
(2) Radiologically, exclusion of the following diseases should be considered: Malignant lymphoma, urinary tract carcinoma, renal infarction, and pyelonephritis (rarely, granulomatosis with polyangiitis, sarcoidosis, and metastatic carcinoma) International Journal of Nephrology cortical and medullary involvement with extension into and beyond the renal capsule, and the presence of plasma cell nests encased by fbrosis, creating a "bird's eye" pattern [43,63,66].However, an abundance of IgG4 + plasma cells in renal tissue alone is not sufciently specifc, as it may also be seen in lupus, Sjogren syndrome, vasculitis (including ANCA-associated vasculitis and hypocomplementemic urticarial vasculitis), diabetic kidney disease, other forms of TIN, chronic pyelonephritis, and lymphoma, which need to be excluded with clinical, imaging, and serologic correlation [43,44,48,67].Histologic features against IgG4-TIN include necrotizing angiitis, granulomatous lesions, neutrophilic infltration, and advanced tubulitis [43].
In practice, clinical, serological, radiographic, and histological features must be considered together.Holistic diagnostic criteria for IgG4-TIN were proposed in 2011 by Raissian and colleagues [48].Teir criteria require the presence of histology compatible with IgG4-TIN plus at least one serologic, radiologic, or extra-renal manifestation suggestive of IgG4-RD [48].An example of histologic IgG4-TIN is depicted in Figure 4.

Glomerular Involvement
Glomerular manifestations of IgG4-RD have also been observed, although to a much lesser degree than IgG4-TIN.Te most common glomerular injury pattern is membranous glomerulonephritis, termed IgG4-related MGN.Te prevalence of this entity is reported as approximately 7% (4/ 58) from two separate case series of patients with IgG4-TIN [34,48].In a key case series of IgG4-related MGN, patients typically presented with nephrotic range proteinuria and elevated serum creatinine, and 56% (5/9) of biopsies had overlapping TIN [68,69].A separate analysis of more than twenty case studies reported a similar 62% prevalence of IgG4-related MGN overlapping with TIN [70].Te pathogenesis of IgG4-related MGN is not fully understood but is likely distinct from the destructive infammatory process in IgG4-RD involving other organs [71].In primary MGN, IgG4 is typically the dominant IgG subclass identifed on kidney biopsy by immunofuorescence with difuse and global granular capillary wall staining, which correlates to subepithelial immune complex deposits on electron   International Journal of Nephrology microscopy [72][73][74].In contrast, MGN in the setting of IgG4-RD has multiple unique features.First, primary MGN is not associated with extra-renal IgG4-RD.Second, storiform fbrosis and lymphoplasmacytic tubulointerstitial infammation are not typical histologic features of primary MGN.Tird, almost all patients with MGN in the setting of IgG4-RD are negative for circulating anti-M type phospholipase A2 receptor (PLA2R) antibody by serology and for PLA2R staining in renal tissue, whereas PLA2R is the most common target antigen in primary MGN [70,75].As a direct result, serum PLA2R antibody positivity is an exclusion criterion in the ACR/EULAR 2019 IgG4-RD Classifcation Criteria [57].Fourth, immunofuorescence for C1q typically shows negative to only segmental and weak granular glomerular capillary wall staining in primary MGN but can have difuse and strong staining in some cases of MGN in IgG4-RD [70,76].Fifth, as compared to IgG4-TIN, IgG4-MGN is more likely to demonstrate an incomplete response to glucocorticoid administration [38,68,70].Collectively, these unique patterns suggest that IgG4-MGN is likely an independent manifestation of IgG4-RD, distinct from primary MGN and distinct from IgG4-TIN, and likely represents an immune complex-mediated glomerulonephritis secondary to IgG4-RD.Te nomenclature of IgG4-related MGN has been proposed [71].Additional glomerular manifestations in IgG4-RD are very rare.Individual case reports have been published describing IgG4-RD associated with immune complexmediated glomerulonephritis with various glomerular injury patterns, including membranoproliferative, mesangial proliferative, endocapillary proliferative, and crescentic patterns [34,[77][78][79][80][81][82][83][84][85].Tere is also the potential for an association with diabetic glomerulosclerosis, as IgG4-related pancreatitis would predispose patients to diabetic kidney disease [64,67].Figure 5 depicts one example of glomerular disease in IgG4-RD on a background of diabetes.Further case reports and the collection of clinical, laboratory, radiologic, and histologic data are needed to better determine the nature of possible relationships between glomerular diseases and IgG4-RD (Appendix).

. Additional Renal Involvement
IgG4-RD may also involve the renal pelvis, urinary tract, and retroperitoneum.In these instances, secondary renal dysfunction may occur due to obstructive hydronephrosis.

Treatment Considerations
Corticosteroids are the bedrock of initial therapy in IgG4-RD, irrespective of the presence or absence of renal involvement.A response to corticosteroids is usually prompt and favourable-a lack of response to steroids ought to evoke consideration of alternate diagnostic possibilities [65,[101][102][103][104].Of note, corticosteroid regimens for IgG4-RD induction vary.A general approach involves oral prednisone at 0.6 mg/kg/day for approximately 4 weeks followed by a gradual taper either to zero or to a maintenance dose to sustain response [103].Serum IgG4 levels, serum complement levels, imaging, and organ-specifc bloodwork (e.g., creatinine) are repeated serially to assess the treatment response.Unfortunately, up to 30% of patients treated with glucocorticoids can experience relapse [102,104].In the setting of IgG4-RKD, there are case reports of patients requiring maintenance hemodialysis and renal transplantation despite glucocorticoid induction therapy [65,105].Hence, early diagnosis and treatment for patients with IgG4-RKD are essential to maximize the chances of renal recovery.Indeed, repeated courses of glucocorticoids for reinduction therapy are undesirable due to the side efects.Hence, steroid-sparing agents, including azathioprine, mycophenolate, and rituximab, among others, have been used for longer-term maintenance therapy [103].Rituximab therapy has the most efcacy data available to date [106,107].Whether a steroid-sparing agent should be initiated at the disease onset with glucocorticoids is controversial and remains a topic of debate [103].In addition, procedural intervention may be required (e.g., ureteric stenting, nephrostomy tube insertion, and biliary stenting), depending on the sites and extent of involvement.In the setting of IgG4-RKD, renal replacement therapy may be necessary in rare cases.However, with treatment, renal function appears to improve readily, with sustained renal recovery on maintenance therapy [65].

Conclusion
Renal manifestations of IgG4-related disease (IgG4-RD) are rich and diverse, yet the disease is likely underdiagnosed.Delays in the diagnosis and treatment of renal manifestations of IgG4-RD can jeopardize the ability to obtain renal recovery.Te primary objective of this review is to improve earlier recognition of IgG4-RD and, in particular, IgG4related renal disease.We recommend that all clinicians who may be involved in the care of patients with IgG4-RD, particularly nephrologists, rheumatologists, general internists, and renal pathologists, consider the possibility of renal involvement in patients with known or suspected extra-renal IgG4-RD.We also recommend that clinicians consider IgG4-RD in the diferential diagnosis of patients with newly identifed renal masses and in patients with idiopathic retroperitoneal fbrosis.Awareness of renal manifestations of IgG4-RD may promote more accurate and timely diagnosis, which, in turn, may improve clinical outcomes for patients.Moving forward, further studies are required to increase our understanding of the epidemiology and pathophysiology of IgG4-RD and the role of diferent immunosuppressive regimens in the therapy of IgG4-related renal disease.

Figure 3 :
Figure 3: Contrast-enhanced computed tomography scan of the abdomen highlighting IgG4-related heterogenous enhancement of the kidneys with hypodensities at the lower pole.Adapted from Korivi et al. [62] as published in the Indian Journal of Nephrology.Reproduced under the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported License.

Figure 4 :
Figure 4: Marked tubulointerstitial efacement highlighted on silver stain in IgG4-RD.Reproduced with permission from PathologyOutlines.com.Figure 5: Granular IgG deposits within glomerular mesangial regions and capillary loops, as well as within tubular basement membranes and Bowman capsule.Background glomerulus shows features suggestive of diabetes.Reproduced with permission from PathologyOutlines.com.

Figure 5 :
Figure 4: Marked tubulointerstitial efacement highlighted on silver stain in IgG4-RD.Reproduced with permission from PathologyOutlines.com.Figure 5: Granular IgG deposits within glomerular mesangial regions and capillary loops, as well as within tubular basement membranes and Bowman capsule.Background glomerulus shows features suggestive of diabetes.Reproduced with permission from PathologyOutlines.com.